Metabolism of nomifensine after oral and intravenous administration Nomifensine (8-amino-1 , 2 ,3 ,4-tetrahydro-2-methy1- 4-phenylisoquinoline maleate; see structure) is a psy- chotropic drug with antidepressant properties. Studies on the biotransformation of nomifensine in man have revealed three principal metabolites: 4-hydroxynomi- fensine (M,), 4-hydroxy-3-methoxynomifensine (M2), and 3-hydroxy-4-methoxynomifensine (M,), which to- gether account for approximately 20% of the drug recovered in urine.' Four other metabolites can be de- tected in urine, but these dihydroxy, dimethoxy, hy- droxydimethoxy, and desmethyl derivatives of nomi- fensine account for only 1% of the total amount of nomifensine.' The metabolism of nomifensine has been studied af- ter single oral doses of 100 mg nomifensineHC-ma- leate in healthy subjects.2 Almost 90% of the given dose was excreted by the kidneys in the first 24 hours after dosing. One third of this was converted into the three main metabolites M,, M2, and M3. The metabo- lites were excreted mainly in a conjugated form, which is very labile in neutral and acidic media and may be converted to free metabolites. Therefore, sodium hy- drogen carbonate was given to the subjects every hour to ensure an alkaline pH value of the urine.2'2 From the Department of Pharmacology, University of Turku. Received for publication Aug. 30, 1985; accepted Dec. 26, 1985. Reprint requests to: Raija Lindberg, M.Sc., Department of Phar- macology, Institute of Biomedicine, University of Turku. Kiina- myllynkatu 10, SF-20520 Turku, Finland. 378 The metabolism of nomifensine was studied after single oral and intravenous administration and after 2 weeks of oral dosing. The three principal metabolites reached maximum plasma concentrations rapidly (in 1 to 1.5 hours) after nomifensine administration. Less than 10% was detected as a free, unconjugated form. All three metabolites were eliminated rapidly (elimination ti,2 values between 6.8 and 9.0 hours). Only very low concentrations of free metabolites were found in plasma after 24 hours of nomifensine administration. AUC values for free metabolites were between 0.27 to 0.46 hr pmol/L after all nomifensine schedules. Two weeks of dosing had no significant influence on the elimination ti,2 or AUC values of the metabolites, indicating no change in the hydroxylation and methylation reactions. In addition, there were no changes in the conjugation reactions during prolonged nomifensine dosing. Nomifensine has a very short ti,2 and no tendency for accumulation after repeated doses. We conclude that nomifensine's clinical pharmacokinetic profile is not significantly changed by the kinetic behavior of its three main metabolites after the usual maintenance doses. (CLIN PHARMACOL THER 1986;39:378-83.) Raija L. P. Lindberg, M.Sc., and Erkka K. G. Syvalahti, M.D. Turku, Finland OH NH2 M1 N-CH3 NH2 NOMIFENSINE NH2 M2 Nomifensine and its three main metabolites In our present investigation, the biotransformation of nomifensine and the formation of its three principal metabolites were studied after single oral and intrave- nous doses of nomifensine. Elimination and excretion into the urine were also evaluated. In addition, the effect of 2 weeks of oral dosing on the metabolism of no- mifensine was studied. In the earlier studies in humans, the principal me- tabolites were separated by TLC and identified by mass spectrometry and nuclear magnetic resonance spec- trometry.1'2 In addition, Sistovaris4 has published a TLC method for the determination of nomifensine metabo- M3